A substantial body of evidence supports the relationship between 5-HT.sub.1c receptor modulation and a variety of diseases and conditions.
The 5-HT.sub.1c receptor subtype was first detected in choroid plexus epithelial cells and is the only 5HT receptor subtype expressed by these cells. Studies of the 5-HT.sub.1c receptor using radioligand binding have been complex due to the cross reactivity of the 5-HT.sub.1c receptor with the 5-HT.sub.2 receptor. The discovery of selective, high affinity compounds which discriminate between 5-HT.sub.1c and 5-HT.sub.2 has been an elusive and important target. Hartig et al., The 5-HT.sub.2 c Receptor Annals New York Academy of Science 149, 159. Compounds with selective affinity for the 5-HT.sub.1c receptor can provide treatment for 5-HT.sub.1c -receptor-mediated conditions without the side effects associated with activity at the 5-HT.sub.2 receptor. Such compounds can simplify characterization of the 5-HT.sub.1c receptor and provide useful new therapeutic agents. In vitro, m-chlorophenylpiperazine (m-CPP) has a slightly higher affinity for the 5-HT.sub.1c sites than for other 5-HT receptors; however, prior to the present invention, there have been no known 5-HT.sub.1c selective ligands.
The activation of the 5-HT.sub.1c receptor has been associated with numerous behavioural and physiological effects. TiPS 11, 181 (May 1990). The 5HT.sub.1c receptors in the limbic system can affect mood, behavior, and hallucinogenesis. Hartig et al., The 5-HT.sub.1c Receptor Annals New York Academy of Science 149, 159. Modulation of the 5HT.sub.1c receptors has been associated with schizophrenia and schizophreniform disorders. Ugedo, L. et. al. Psychopharmacology, 98, 45 (1989); Canton H. et. al. Eur. J. Pharmacol. 191, 93 (1990). Hypothalamic 5-HT.sub.1c receptors can influence sleep, appetite, thermoregulation, sexual behavior, motor activity, and neuroendocrine function. Hartig et al., The 5-HT.sub.1c Receptor Annals New York Academy of Science 149, 159. Additionally, studies indicate that 5-HT.sub.1c receptors mediate hypoactivity, caused decreased feeding in rats, and have anxiogenic effects. Id. Studies have shown that drug-induced penile erections are 5-HT.sub.1c mediated. Psychopharmacology 101, 57 (1990). Likewise, 5-HT.sub.1c modulation can treat or prevent priapism.
Other studies have used m-CPP to characterize responses associated with 5-HT.sub.1c receptors. Although responses to 5-HT.sub.1c are difficult to characterize by this method, the studies evince that 5-HT.sub.1c receptors influence the onset of anxiety, obsessive-compulsive disorders, panic disorders, Gilles de la Tourette syndrome and migraine headaches. TiPS 11, 181 (May 1990). The studies indicate that the 5-HT.sub.1c receptor can be involved in Alzheimer's disease as well. Id. The 5-HT.sub.1c receptor is involved in the modulation of the balance of cerebrospinal fluid. Further, the 5-HT.sub.1c receptor is associated with the sensation of pain. Zemlan, F. P. et al. Neurochem. Int. 16, 507 (1990).
It would be advantageous to have compounds which would permit modulation of the 5-HT.sub.1c receptor. It would be particularly desirable to have compounds with high 5-HT.sub.1c receptor affinity and low 5-HT.sub.2 receptor affinity. It would be further advantageous to have compounds that minimize the effects of eating disorders, sexual disorders, and other disorders or conditions associated with 5-HT.sub.1c modulation.